Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 22, Issue 6, Pages 458-U46Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3016
Keywords
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Funding
- Cancer Research UK [C20724/A14414]
- Wellcome Trust [097301/Z/11/Z, 090532/Z/09/Z, 101584MA]
- Wellcome Trust
- [FP7-328531]
- Cancer Research UK [14414] Funding Source: researchfish
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Repulsive guidance molecules (RGMs) control crucial processes including cell motility, adhesion, immune-cell regulation and systemic iron metabolism. RGMs signal via the neogenin (NEO1) and the bone morphogenetic protein (BMP) pathways. Here, we report crystal structures of the N-terminal domains of all human RGM family members in complex with the BMP ligand BMP2, revealing a new protein fold and a conserved BMP-binding mode. Our structural and functional data suggest a pH-linked mechanism for RGM-activated BMP signaling and offer a rationale for RGM mutations causing juvenile hemochromatosis. We also determined the crystal structure of the ternary BMP2-RGM-NEO1 complex, which, along with solution scattering and livecell super-resolution fluorescence microscopy, indicates BMP-induced clustering of the RGM-NEO1 complex. Our results show how RGM acts as the central hub that links BMP and NEO1 and physically connects these fundamental signaling pathways.
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